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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

The Personalized Therapies in Lung Cancer Conference: Part 2
Fri, 03/21/2014 - 13:46
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

After a full morning, this conference has a nice feature during the lunch break of having the faculty all sit at separate tables so that attendees can ask questions of them. It’s nice to break through the silos that typically have the faculty sit and talk together, which may create a barrier to having these important conversations between the meeting attendees and the few on the faculty. Also during the lunch break is a concurrent nursing session on the growing role of the nurse navigator and oncology nurses in a new era of personalized treatment recommendations.

The afternoon sessions then kicked off with Dr. Roy Herbst from Yale, reviewing mesenchymal-epithelial transition (MET) as a target in lung cancer. He described the work on the MET oral small molecule inhibitor tivantinib. It had looked favorable when combined with Tarceva (erlotinib) in a phase II study before becoming the subject of a phase III study that was unfortunately discontinued after early results showed it would not make significant improvement in overall survival (OS), even though progression-free survival (PFS) was improved in the phase II study. In contrast, we still await results of a completed phase III trial of Tarceva +/- the IV monoclonal antibody to MET, onartuzumab (or METMAb), which also showed good results for the combination, though only in the half of patients with significant MET protein expression on their cancer cells. He also made mention of several MET inhibitors still in early development that we hope to see in clinical trials for lung cancer.

GRACE faculty member Dr. Heather Wakelee from Stanford covered the topic of anti-angiogenesis (inhibiting blood vessel support for tumors), starting with a historical walk through the data on Avastin (bevacizumab), currently approved for a subset of patients with non-squamous non-small cell lung cancer (NSCLC). She then turned to novel (targeted) anti-angiogenic agents such as ramucirumab, (IMC-1121B), another monocolonal antibody with significant anti-angiogenic activity that is the subject of the REVEL study, a phase III trial randomizing patients with any NSCLC subtype to second line Taxotere (docetaxel) with or without ramucirumab. The trial completed enrollment in late 2013. There are also several oral anti-angiogenic agents, with second line nintedanib combined with Taxotere having demonstrated improved survival compared with Taxotere alone in patients with advanced lung adenocarcinoma on the LUME-Lung 1 trial.  She also noted that the ECOG 1505 trial of adjuvant chemotherapy with or without Avastin has completed enrollment, so we should learn in the next few years whether it improves survival compared with chemotherapy alone after surgery for early stage NSCLC patients.

Dr. Ed Kim from the Levine Cancer Center in Charlotte, NC spoke on MEK inhibitors to target KRAS mutations, the most common molecular markers we see in lung cancer (about 20-25% of patients). The oral agent selumetinib generated a lot of excitement in recent years for its apparent activity combined with Taxotere in KRAS mutation-positive patients. It is now the subject of a global phase III randomized trial comparing Taxotere/selumetinib to Taxotere alone in this setting. Another oral MEK inhibitor, trametinib, is also being combined with chemotherapy, and it still needs to be clarified whether it is clearly more effective than chemotherapy alone, and whether MEK inhibitors should be targeted to patients with a KRAS mutation or not. There is also a question of whether activity of MEK inhibitors is greater for some particular KRAS mutations and not others, but that needs to be clarified further.

The last portion of the day focused on immunotherapy. Dr. Herbst set the table with a review of the science of immune checkpoint inhibitors. He noted that antibody inhibitors of both programmed death receptor-1 (PD-1, on immunologic host T cells) and its ligand protein (PDL1, on tumor cells) are in development and have demonstrated very promising and long-lasting activity in a wide range of patients and lung cancer histologies. Activity seems especially probable in the subset of patients with significant PDL1 expression on their tumor cells (depending on the technique and grading system used, 20-50% of patients with NSCLC), though responses are also seen in a smaller proportion of patients negative for PDL1 expression on their tumors. Similar results have been seen with nivolumab (anti-PD1), MPDL3280A (anti-PDL1), and most recently MK-3475 (anti-PD1), with others moving quickly into clinical testing as well.

I then followed with a discussion of vaccine approaches as an immunotherapy alternative beyond the immune checkpoint inhibitors. Reminding the audience that immunotherapies had emerged as promising before the anti-PD1 and anti-PDL1 therapies emerged a couple of years ago, I described the large MAGRIT trial of adjuvant MAGE-A3 vaccine for the approximately 1/3 of early stage NSCLC patients who have MAGE-A3 protein/antigen expression on their tumors and who were randomized to the MAGE-A3 vaccine or placebo. This trial of over 2,000 patients from over 6,000 screened has been completed, and we just learned that the trial failed to demonstrate a benefit for the general population or the subset of patients who hadn't received adjuvant chemotherapy; we await the results of the trial that looked at outcomes based on a gene signature that may predict for significant benefit with the vaccine. For patients with stage III NSCLC, tecemotide (also known as L-BLP-25), which targets MUC-1 mucin on tumor cells, was tested vs. placebo after chemo/radiation in the START trial. Though the overall trial was negative for a significant difference, the subset of patients who received concurrent chemo/radiation and then tecemotide had a provocatively longer survival than those who received placebo – this may lead to a subsequent trial that focuses only on patients with locally advanced (stage III) NSCLC and first receive concurrent chemo/radiation. And then along with the START trial was the STOP trial of Lucanix (belagenpumatucel), the whole tumor cell vaccine from 4 irradiated cryopreserved (frozen) cell lines, which is being tested as a maintenance therapy for patients with stage III or IV NSCLC who have achieved a response or stable disease after initial chemotherapy.  With no results reported despite being launched in 2008, the STOP trial is one that I have only become more dubious about with every passing year of no news about it.

The conference then featured two talks from people who don’t often have an opportunity to present at such meetings but are indispensable members of the team for delivering good cancer care. Marianne Davies, an oncology nurse at Yale, described the myriad side effects that they have seen there with immunotherapies. From GI to lung to endocrine to general constitutional symptoms like fever and fatigue, she covered the leading problems encountered with immunotherapies, as well as ideas on management. Then Dr. Val Adams, a PharmD from the University of Kentucky, reminded us of the value of a good PharmD in helping manage side effects and dietary issues with so many new oral targeted therapies. Having someone able to provide thorough insight about potential drug interactions, offer ideas like preventive doxycycline to reduce rash in someone who will be out in sunlight while on Tarceva, etc. is a great benefit for oncologists and patients.

The day’s events closed with a lighthearted debate between the chairs, Drs. Paul Bunn and Roy Herbst, about whether genomic sequencing should become routine as part of the initial workup of patients with advanced NSCLC. Though the audience began strongly favoring this idea, perhaps as the ultimate step in personalized care for lung cancer (80% in favor of genomic sequencing pre-debate), and Dr. Herbst argued well for its potential value, Dr. Bunn made compelling arguments that more limited testing provides advantages of well standardized tests with faster turnaround times for all of the identified markers for which we have an actual treatment to offer. The post-debate survey found a much narrower margin in favor of broad genomic testing (55% pro, 45% against), highlighting that the issue is more complex than just “more is better” for marker testing.

In an era in which the number of conferences has been pruned over the past few years, the Annual Symposium on Personalized Therapies and Best Clinical Practices for Lung Cancer remains one of the most relevant and innovative. With an approach that intermingles cases with new information being presented, a great combination of speakers from different fields and institutions, a focus on the new world of targeted therapies, and a nice time and location of southern California in the fall, it’s a conference I now hope to attend every year. We’ll probably try to integrate some patient-based forums around it in the next year or so, perhaps on timely topics like immunotherapy and acquired resistance mechanisms and treatments.  Maybe we’ll see some of you there!

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